scholarly journals Therapeutic Targeting of Protein Kinase CK2 Gene Expression in Feline Oral Squamous Cell Carcinoma: A Naturally Occurring Large-Animal Model of Head and Neck Cancer

2017 ◽  
Vol 28 (2) ◽  
pp. 80-86 ◽  
Author(s):  
Claire M. Cannon ◽  
Janeen H. Trembley ◽  
Betsy T. Kren ◽  
Gretchen M. Unger ◽  
M. Gerard O'Sullivan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
Animal Model ◽  
Head And Neck Cancer ◽  
Protein Kinase Ck2 ◽  
Large Animal Model ◽  
Large Animal ◽  
Therapeutic Targeting ◽  
Naturally Occurring ◽  
Kinase Ck2

Naturally-Occurring Antibodies to Human AAV In Sheep: A New Large Animal Model for Immune Aspects of AAV Gene Transfer.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3762-3762
Author(s):  
Joseph Tellez ◽  
Jonathan D. Finn ◽  
Nicholas Tschernia ◽  
Graca Almeida-Porada ◽  
Valder Arruda ◽  
...  
Keyword(s):  
Animal Model ◽  
Conflicts Of Interest ◽  
High Titer ◽  
Cell Epitope ◽  
Model System ◽  
Large Animal Model ◽  
Preclinical Model ◽  
Large Animal ◽  
Target Tissue ◽  
Naturally Occurring

Abstract Abstract 3762 AAV vectors have received a great deal of attention for clinical gene therapy (GT), since they transduce many mitotic and quiescent cells and mediate long-term transgene expression. Unfortunately, many of the serotypes of AAV commonly employed in GT procedures ubiquitously infect humans, generating pre-existing immunity against the AAV capsid proteins that precludes efficient transduction or induces CTL responses to the transduced target tissue. At present, highly successful animal studies have not translated into clinical success in humans, due, at least in part, to the paucity of animals which harbor endogenous antibodies which recognize and bind AAV-2 and other AAV serotypes for which humans are the natural host. Sheep have long been used as a model to study a broad range of disease states, and a high degree of clinical predictability has consistently been observed. We therefore examined whether sheep possess antibodies to AAV and could thus serve as a much-needed preclinical model system for evaluating AAV-based GT. ELISAs were performed on sera from a panel of 6 healthy Merino-Rambouillet sheep using AAV-1,-2,-5,-6,-8, -9 particles as the antigen. Our results demonstrate that sheep naturally harbor antibodies to all 6 AAV serotypes tested, yet the titers against the different serotypes varied greatly from sheep-to-sheep. While one sheep exhibited very high level (>2300ng/ml) IgG against all 6 AAV serotypes tested, others exhibited moderate/low (>350ng/ml) IgG against all 6 AAV serotypes, and still others exhibited moderate/low level IgG against only 3–4 of the tested serotypes. Despite these differences, all sheep harbored detectable antibodies to AAV 2, 5, & 8. A luciferase-based neutralizing antibody (NAB) assay was then performed on sera from 3 of the sheep exhibiting the highest titer IgG against AAV 2, 8, & 9 to assess the clinical significance of these antibodies in the context of AAV-based GT. All 3 animals harbored relatively high titer (1:100-1:316) NAB to AAV 2, but only 1 animal harbored significant NAB titers against AAV 8 & 9 (1:31, and 1:100, respectively). B cell epitope mapping of these 3 animals with a library of peptides derived from the capsids of AAV 2, 5, 8, and 9 revealed that each individual sheep harbored antibodies recognizing from 17 to 50 of the various capsid-derived peptides, some of which were common to all capsids, and some of which were unique to specific AAV serotypes. Importantly, many of the identified capsid epitopes have also been shown to be recognized by antibodies present in human patients with existing AAV immunity. To our knowledge, this is the first report of an animal disease model harboring naturally occurring functional antibodies to serotypes of human AAV commonly employed as GT vectors. The close parallels between human and sheep physiology, coupled with our recent re-establishment of sheep with severe hemophilia A with a null mutation in the FVIII gene and the presence of these antibodies, suggest that sheep may represent an ideal large animal model system in which to study GT in the context of pre-existing immunity to AAV, and to develop novel strategies for circumventing this immunologic barrier. Disclosures: No relevant conflicts of interest to declare.

Gene Transfer of Canine FVIIa Results in Partial Correction of Canine Hemophilia: A Model for FVIII/FIX Gene-Based Bypassing Agents.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 195-195 ◽  
Author(s):  
Paris Margaritis ◽  
Elise Roy ◽  
Harre D. Downey ◽  
Shangzen Zhou ◽  
Elizabeth Merricks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Model ◽  
Gene Transfer ◽  
Hemophilia A ◽  
Active Form ◽  
Factor Ix ◽  
Factor Vii ◽  
Large Animal Model ◽  
Large Animal ◽  
Partial Correction

Abstract Despite its extensive use particularly in the management of hemophilic inhibitor patients, recombinant Factor VIIa (rhFVIIa) infusion has important limitations stemming from the nature of FVIIa itself, since its short half-life necessitates repeated injections and also carries high treatment costs. To overcome these, we have designed a gene transfer approach using a modified FVII transgene that is cleaved intracellularly and secreted in the active form, FVIIa. Using the human and murine analogue of this engineered transgene we have shown phenotypic correction of hemophilia B mice, following adeno-associated virus (AAV) - mediated, liver-directed gene delivery (Margaritis et al., 2004). In order to demonstrate efficacy in a large animal model of hemophilia, we cloned the canine Factor VII cDNA and generated the canine homologue of our modified transgene (cFVIIa). Recombinant cFVII zymogen and cFVIIa were purified and characterized in vitro in a clotting-based assay using canine reagents only (activated partial thromboplastin time [aPTT]). We found that cFVIIa had activity indistinguishable from rhFVIIa, while cFVII zymogen had negligible activity (5% rhFVIIa). In order to demonstrate in vivo efficacy, we produced 4 lots of an AAV8-based vector directing liver-specific expression of cFVIIa with similar vector titers (2–5 E13 vector genomes [vg]/ml). In hemophilia A (HA) or B (HB) mice, tail-vein delivery of 0.3 – 1.2 E12 vg/mouse (1.2 – 4.8 E13 vg/kg) resulted in long-term normalization of the hemophilic phenotype, demonstrating that cFVIIa can correct the defect in murine hemophilia. We proceeded to infuse 4 hemophilia dogs, with increasing vector doses: HB male (2.06 E13 vg/kg); HA male (6.25 E13 vg/kg); HA female (1.25 E14 vg/kg); HA male (1.25 E14 vg/kg). None of the dogs showed any adverse effects following vector delivery at any dose (the initial HB dog has been followed for almost 2 years [ongoing]). We followed the level of gene expression by clotting assays (prothrombin time [PT]/aPTT) and whole blood clotting time (WBCT). The initial dose of 2.06 E13 vg/kg resulted in a transient reduction in the PT/aPTT/WBCT. A considerable and sustained reduction in PT (18 sec, normal is ∼25 sec), aPTT (19 sec, normal is ∼30 sec, hemophilic is >40sec) and WBCT (25min, normal is ∼15min, hemophilic is >40min) was observed following administration of 6.25 E13 vg/kg in an HA male dog. Two more HA dogs were infused with 1.25 E14 vg/kg (male and female). The female HA dog exhibited only a modest decrease in aPTT (22sec), despite the vector dose increase, and a reduction in WBCT (30min), an observation that could be due to previously described gender-specific effects on gene expression. From preliminary and ongoing observations, the male HA dog infused also exhibited a decrease in WBCT. As an efficacy endpoint, the dogs exhibited a total of 3 bleeding episodes (none likely to be spontaneous, occurred in the lowest dose HB dog) in a cumulative time period of 38.5 months, compared to the expected 16 episodes (Brunetti-Pierri et al., 2005). In summary, our results demonstrate for the first time that gene transfer using a Factor VIII/Factor IX bypassing agent (canine FVIIa) can result in partial correction of the hemophilic phenotype in a large animal model of hemophilia.

Characterizing Canine Lymphoma As a Potential Large Animal Model of Human Diffuse Large B-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5193-5193 ◽  
Author(s):  
Kristy L. Richards ◽  
Alison Motsinger-Reif ◽  
Hsiao-Wei Chen ◽  
Yuri D. Fedoriw ◽  
Cheng Fan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Model ◽  
B Cell ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
B Cell Lymphoma ◽  
Large Animal Model ◽  
Large Animal ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 5193 Diffuse large B-cell lymphoma (DLBCL) affects ∼25,000 people in the U.S. each year, and fewer than half of them are cured with standard therapy. DLBCL can be divided into two subtypes by gene expression profiling, germinal center B-cell (GCB) type and activated B-cell (ABC) type. ABC-type DLBCL patients have significantly poorer outcomes. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL is one of the most common cancers in veterinary oncology. Similar to human DLBCL patients, dogs with lymphoma are treated with both CHOP-like regimens and autologous stem cell transplants. Morphologically, canine lymphomas are similar to hDLBCL, with shared histologic markers, such as CD20 and PAX5. With recent technologies based on knowledge of the canine genome sequence, it is now possible to evaluate dogs as a potential large-animal model for hDLBCL. We evaluated 58 canine B-cell lymphomas by generating comprehensive gene expression profiles and comparing them to previously published hDLBCL expression profiles. Canine B-cell lymphoma expression profiles were similar in some ways to hDLBCLs. For instance, increased expression of NF-kB pathway genes was noted in a subset of lymphomas, mirroring NF-kB pathway activation in human ABC-type DLBCL. Furthermore, immunoglobulin heavy chain (IGH) mutation status, which is correlated with ABC/GCB cell of origin in hDLBCL, separated canine DLBCL into two groups with statistically different progression-free and overall survival times. However, canine DLBCL differed from hDLBCL in other aspects, including rare immunohistochemical positivity for BCL6 and MUM1/IRF4. Collectively, these results define aspects of canine B-cell lymphomas that resemble hDLBCL, identifying molecular similarities that could allow dogs to be used as a representative model of hDLBCL. Further comparative studies, including therapeutic trials, could potentially improve outcomes in both species. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Naturally occurring cardiomyopathy in the Doberman pinscher: A possible large animal model of human cardiomyopathy?

1990 ◽  
Vol 16 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Mark L. Smucker ◽  
Sanjiv Kaul ◽  
Jerry A. Woodfield ◽  
James C. Keith ◽  
Scott A. Manning ◽  
...  
Keyword(s):  
Animal Model ◽  
Large Animal Model ◽  
Large Animal ◽  
Doberman Pinscher ◽  
Naturally Occurring

scholarly journals Naturally-occurring myopia and loss of cone function in a sheep model of achromatopsia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Maya Ross ◽  
Ron Ofri ◽  
Itzhak Aizenberg ◽  
Mazen Abu–Siam ◽  
Oren Pe’er ◽  
...  
Keyword(s):  
Animal Model ◽  
Axial Length ◽  
Statistical Tests ◽  
Red Light ◽  
Large Animal Model ◽  
Large Animal ◽  
Sheep Model ◽  
Awassi Sheep ◽  
Naturally Occurring ◽  
Cone Function

Abstract Achromatopsia is an inherited retinal disease characterized by loss of cone photoreceptor function. Day blind CNGA3 mutant Improved Awassi sheep provide a large animal model for achromatopsia. This study measured refractive error and axial length parameters of the eye in this model and evaluated chromatic pupillary light reflex (cPLR) testing as a potential screening test for loss of cone function. Twenty-one CNGA3 mutant, Improved Awassi, 12 control Afec-Assaf and 12 control breed-matched wild-type (WT) Awassi sheep were examined using streak retinoscopy and B-mode ocular ultrasonography. Four CNGA3 mutant and four Afec-Assaf control sheep underwent cPLR testing. Statistical tests showed that day-blind sheep are significantly more myopic than both Afec-Assaf and WT Awassi controls. Day-blind sheep had significantly longer vitreous axial length compared to WT Awassi (1.43 ± 0.13 and 1.23 ± 0.06 cm, respectively, p < 0.0002) and no response to bright red light compared to both controls. Lack of response to bright red light is consistent with cone dysfunction, demonstrating that cPLR can be used to diagnose day blindness in sheep. Day-blind sheep were found to exhibit myopia and increased vitreous chamber depth, providing a naturally occurring large animal model of myopia.

scholarly journals Cardiopulmonary remodeling in fattened beef cattle: a naturally occurring large animal model of obesity-associated pulmonary hypertension with left heart disease

2018 ◽  
Vol 9 (1) ◽  
pp. 204589401879680 ◽  
Author(s):  
Greta M. Krafsur ◽  
Joseph M. Neary ◽  
Franklyn Garry ◽  
Timothy Holt ◽  
Daniel H. Gould ◽  
...  
Keyword(s):  
Animal Model ◽  
Pulmonary Hypertension ◽  
Heart Disease ◽  
Beef Cattle ◽  
Left Ventricular ◽  
Large Animal Model ◽  
Large Animal ◽  
Left Heart ◽  
Naturally Occurring ◽  
Left Heart Disease

The obesity epidemic in developed societies has led to increased cardiovascular diseases including pulmonary hypertension associated with left heart disease (PH-LHD), the largest and fastest-growing class of PH. Similar to obese humans, PH and heart failure (HF) are increasingly recognized in North American fattened beef cattle. We hypothesized that PH and HF in fattened beef cattle are novel, phenotypically distinct manifestations of bovine PH arising from left ventricular (LV) dysfunction similar to obesity-related PH-LHD in humans. We conducted a semi-quantitative histopathological assessment of cardiopulmonary tissues obtained from fattened beef cattle suffering end-stage HF compared to asymptomatic cattle of equivalent age undergoing the same fattening regimens. In HF animals we observed significant LV fibrosis, abundant cardiac adipose depots, coronary artery injury, and pulmonary venous remodeling recapitulating human obesity-related PH-LHD. Additionally, striking muscularization, medial hypertrophy, adventitial fibrosis, and vasa vasorum hyperplasia in the pulmonary arterial circulation were associated with sequela of pathologic right ventricular (RV) remodeling suggesting combined pulmonary venous and arterial hypertension. The association between obesity, pathologic cardiopulmonary remodeling, and HF in fattened beef cattle appears to recapitulate the complex pathophysiology of obesity-associated PH-LHD in humans. This novel, naturally occurring, and large animal model may provide mechanistic and translational insights into human disease.

DEVELOPMENT OF A LARGE ANIMAL MODEL OF OPIATE ADDICTION TO EVALUATE CARDIOVASCULAR FUNCTION.

Analgesia ◽  
1995 ◽  
Vol 1 (4) ◽  
pp. 598-602 ◽  
Author(s):  
L.D. Napier ◽  
Z. Mateo ◽  
D.A. Yoshishige ◽  
B.A. Barron ◽  
J.L. Caffrey
Keyword(s):  
Animal Model ◽  
Cardiovascular Function ◽  
Large Animal Model ◽  
Opiate Addiction ◽  
Large Animal
Sign in / Sign up

Export Citation Format

Share Document